By examining common genes in three disparate species – axolotls, mice and zebrafish – scientists have discovered the potential for new gene therapies that could ultimately be used to regenerate human limbs, according to a new study published this week.
“This important study brought together three laboratories and worked across three organisms to compare regeneration,” said Josh Currie, assistant professor of biology at Wake Forest. The same laboratory studies the Mexican axolotl salamander. “It showed that there is a universal, unifying genetic program that drives reproduction in very different species, such as salamanders, zebrafish, and mice.”
The study, published in the Proceedings of the National Academy of Sciences, included plastic surgeons David A. Brown, who studies mouse finger regeneration at Duke University, and Kenneth D. Poth, who studies zebrafish fin regeneration at the University of Wisconsin-Madison.
According to the annual Global Burden of Disease Statistics, more than 1 million limb amputations occur worldwide due to vascular diseases such as diabetes, trauma, cancer, and infections. That number is expected to increase further as the population ages and the number of diabetes diagnoses increases.
This pressing challenge led Brown, Currie, and Poss to explore treatments that go beyond prosthetics: alternatives to the complex sensory and motor skills of real limbs.
They may have found a solution in something called the SP gene. Scientists have discovered that this gene is essential for limb regeneration and is shared by mice, zebrafish and axolotls.
Treatment to replace defective genes
Scientists chose to study these three animals for a specific reason:
- of axolotl He has excellent regenerative abilities and has the ability to completely regenerate limbs. Tail containing spinal cord. Parts of the heart, brain, liver, lungs, and jaw.
- zebrafish The caudal fin provides one of the best models for appendage regeneration because it regrows rapidly and has unlimited regrowth potential. Zebrafish can also regenerate the heart, spinal cord, brain, retina, kidneys, and pancreas.
- mouse They correspond to mammals like humans and can already regenerate the tips of their fingers. Humans can also regrow their fingertips even after injury if the nail bed is preserved. This allows for the regeneration of flesh, skin, and bones.
Professor Currie said once the scientists confirmed that the regenerating epidermis, or skin, of all three species expressed the SP genes SP6 and SP8, they began testing what the genes did and how they functioned.
Biology doctoral student Tim Curtis Jr. contributed to research in the Curry lab with assistance from undergraduate student Elena Singer Freeman, a Goldwater Scholar and 2025 Wake Forest Biochemistry and Molecular Biology graduate.
Emulate the genetic abilities of salamanders
In salamanders, SP8 functions to regenerate limbs. Using CRISPR gene editing technology, Curry’s lab deleted SP8 from the axolotl genome. Without SP8, axolotls could not properly regenerate bones in their limbs. Similar results occurred when mouse digits were missing in SP6 and SP8.
Armed with that information, Brown’s lab developed a viral gene therapy using tissue regeneration promoters found in zebrafish.
The treatment delivered a secreted molecule called FGF8, a gene normally turned on by SP8, which promoted finger bone regeneration and partially reversed the regenerative effects of the missing SP gene in the mice.
Human limbs do not have such regenerative powers, but treatments that emulate the SP gene’s ability may one day be able to do so.
We can use this as a kind of proof-of-principle that we may be able to provide an alternative treatment to this regeneration style of epidermis in human tissue regeneration. ”
Josh Currie, Wake Forest Assistant Professor of Biology
Building the foundation for human treatment
More research is needed to translate the results from mouse digits into human limbs, but Professor Currie said the work lays the foundation for the search for treatments to regenerate limbs after injury or disease.
“Scientists are pursuing many solutions for limb replacement, including bioengineered scaffolds and stem cell therapy,” Professor Currie explained. “The gene therapy approach in this study is a new tool that can complement and potentially expand what will one day be a multidisciplinary solution to regenerate human limbs.”
He said the decision to collaborate between scientists studying such different animals made a big difference in the study.
“A lot of times, scientists work in silos. We only study axolotls, or we only study mice, or we only study fish,” Currie said. “What really stands out about this work is that we’re working with all these different organisms. This is very powerful and I hope we’ll see more of it in this field.”
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Reference magazines:
Brown, D.A. Others. (2026). Enhancer-directed gene delivery for finger regeneration based on conserved epidermal factors. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2532804123. https://pnas.org/doi/10.1073/pnas.2532804123
